The present invention relates to ligands, transition metal complexes including the ligands, and methods of using the ligands and transition metal complexes. More particularly, the invention relates to ligands including first and second heteroatoms, transition metal complexes of such ligands, and methods of using the ligands and complexes, for example, to facilitate chemical reactions, such as hydration of terminal alkynes.
Medicinal chemists and biochemists want to know how amino acids are arranged in proteins, so that they can better understand the correlation between structures and the functions of drugs. One of the techniques used to accomplish the task of protein structure determination requires the breaking of amide bonds to liberate the amino acids. However, at physiological temperatures and pH 9, it takes an impractical length of time, for example, 168 years, to break half the amide bonds in a sample. In contrast, organisms found in nature have remarkably efficient systems to make and break amide bonds. Scientists have used natural enzymes such as carboxypeptidase to do the task of amide bond cleavage.
In some cases, it is believed that the crucial step involves proton transfer between imidazole, a carboxylate, and the amide undergoing hydrolysis, while other enzymatic systems involve a metal-catalyzed amide bond cleavage such as that seen in the zinc(II)-metalloprotease. However, existing enzymatic systems can be very complicated and sometimes difficult to handle due to their sensitivity to temperature and pH.
Amide hydrolysis has been catalyzed not only by enzymes, but also by acids, bases, and metal ions. These systems take advantage of one or more possible factors, which facilitate amide bond cleavage. First, the amide bond cleaving reagent or catalyst could act as a proton transfer reagent, which can be an important factor in amide bond hydrolysis. Secondly, a metal may catalyze or mediate amide hydrolysis by acting as a Lewis acid through O-complexation, delivery of a metal-coordinated hydroxide or a combination of the latter two processes.
Considerable work has been directed toward studying the amide hydrolysis reaction and the development of reagents that assist amide hydrolysis. Some work toward the development of an amide hydrolysis catalyst has been published by Kostic. For example, Kostic and coworkers have found that a palladium(II) complex can accomplish the hydrolysis of a number of dipeptides, but with only a modest 4 catalytic turnovers.
It would be advantageous to provide reaction facilitators, e.g., catalysts, promoters and the like, that mimic enzymatic systems in their hydrogen-bonding and/or proton transfer abilities, but are robust, simple to handle, and have useful reactor facilitation.
Industrial hydrolysis of acrylonitrile is used to make acrylic acid which, in turn, can be converted to a variety of esters such as methyl, ethyl, butyl, and 2-ethylhexyl acrylates. The acrylates can then be used as comonomers with methyl methacrylate and/or vinyl acetate to give polymers for water-based paints, among other products. A number of industrial methods exist for obtaining acrylic acids from nitriles and one of the more economical methods is the direct hydrolysis of the acrylonitrile to the acrylic acid. However, this synthetic route involves the use of a stoichiometric amount of sulfuric acid to produce the acrylamide sulfate, which is then treated with an alcohol to give the acrylic ester. It would be advantageous to provide a direct route from the acrylonitrile and alcohol to yield the desired acrylate without the need to use and then neutralize a strong acid.
As petroleum resources dwindle and the need to control the emissions of carbon dioxide into the environment increases, use of carbon dioxide as a feedstock becomes more desirable. It would be advantageous to provide materials useful to facilitate carbon dioxide conversion, for example, to carbonates, carbamates and ureas.
A further example of environmentally desirable methods of conducting organic synthesis involves the use of water in the oxidation of unsaturated hydrocarbons. For example, the metal-catalyzed hydration of alkynes is an important route to carbonyl compounds. The use of water in such syntheses has the additional advantages of ease of use, safety, and economic savings. Most metal-catalyzed hydrations of 1-alkynes follow Markovnikov addition to give ketones. Recently, anti-Markovnikov addition has been reported, which gives aldehydes and a small amount of ketones [Tokunaga, M., et al. Angew. Chem. Int. Ed., 37(20), 2867-2869 (1998); JP 11319576].
It is desirable to identify and exploit the novel cooperativities afforded by metal ions and suitable organic ligands in additional industrial processes, for example, in the hydration of terminal alkynes. It is preferred that such reactions be catalytic in nature so that the organometallic complex is not consumed during the reaction.
New organic ligands, transition metal complexes including such ligands and methods for using the ligands and complexes have been discovered. The present ligands and transition metal complexes can be produced using relatively straightforward synthetic chemistry techniques. Moreover, the structures of the present ligands and metal complexes can be effectively selected or even controlled, for example, in terms of proton transfer ability and/or hydrogen bonding ability, thereby providing ligands and complexes with properties effective to facilitate one or more chemical reactions. Thus, the present metal complexes can be effectively used to facilitate, for example, catalyze, promote, and the like, various chemical reactions, such as hydrolysis, alcoholysis, aminolysis, carbon dioxide conversion, and hydration reactions, which provide useful benefits.
In one broad aspect of the present invention, compositions are provided which comprise at least one organic ligand and a transition metal moiety partially complexed by the organic ligand.
The present organic ligands, many of which themselves are novel and within the scope of the invention, include a first heteroatom and a second heteroatom. The first and second heteroatoms are covalently bonded to each other or separated from the other by at least one atom, for example, a carbon atom. Whenever the present organic ligands are complexed to a transition metal moiety, one or both of the first and second heteroatoms is/are covalently bonded to the transition metal moiety. In particular, each of the first and second heteroatoms presents a lone pair of electrons that can be free (unbonded), protonated, occasionally or temporarily bonded to an aforementioned transition metal moiety, e.g., through a coordinate covalent bond, or hydrogen bonded to a second molecule, e.g., water. It is this variability in functionality that affords the desired cooperativity sought in a ligand of the invention, especially whenever catalytic activity is desired.
In one embodiment of the invention, a composition includes an organic ligand having the following structure: 
In this molecule, one or more of the pyridyl N atoms binds to a transition metal moiety, for example, containing ruthenium.
In a further aspect of the invention, an organic compound includes at least two different types of heteroatoms selected from among N, P, and S, and further includes at least one substituted or unsubstituted heterocycle selected from imidazole, pyrazole, and pyridine groups. In this molecule, the at least two different types of heteroatoms are separated from each other by at least one atom, e.g., a carbon atom. The heteroatoms are preferably selected so that at least one is capable of binding to a transition metal and another has a binding affinity for water through a hydrogen bond.
In another preferred embodiment, a ligand of the invention includes an N-heterocycle covalently linked to a P-atom. A particularly preferred ligand in this regard is a P-linked imidazole having the formula shown below: 
Whenever an aforementioned P-linked imidazole is coordinated to Ru in a transition metal complex for use in the anti-Markovnikov hydration of 1-alkynes, it is preferred that R1, R2, and R3 are independently selected from hydrogen or alkyl, and R is alkyl or aryl. Most preferably, the ligand has R1=t-butyl, R2=methyl, R3=H, and R=phenyl.
The present organic ligands can be very effectively structured and adapted to control the proton transfer ability and/or hydrogen bonding ability of the transition metal complex of which the ligand is a part. In other words, the present ligands can be selected to obtain the desired degree of proton transfer ability and/or hydrogen bonding ability so that the resulting transition metal complex is highly effective in performing a desired chemical transformation, for example, hydrolysis, alcoholysis, aminolysis, carbon dioxide conversion, and addition of water, alcohols, ammonia or amines to alkenes and alkynes. Such reactions are typically performed by a cooperativity between one heteroatom binding the transition metal and a second heteroatom of the ligand performing H atom transfers with one or more reactants.
In an additional broad aspect of the present invention, methods for reacting alkenes or alkynes with water, alcohols, ammonia or amines are provided. Such methods comprise contacting the reactants in the presence of a transition metal complex of the invention in an amount effective to facilitate the desired reaction to one or more desired products. The contacting occurs at effective reaction conditions. In a particularly preferred method, terminal alkynes are catalytically converted to aldehydes with high selectivities at or near neutral pH.
Each feature and combination of two or more features described herein are included within the scope of the present invention provided that any two features of any such combination are not mutually inconsistent or incompatible.
These and other aspects and advantages of the present invention are set forth in the following detailed description, examples and claims.
In one aspect, the present invention is directed to organic ligands including a first heteroatom and a second heteroatom directly bonded to the first heteroatom or located one carbon atom away from the first heteroatom. Exemplary heteroatoms include nitrogen atoms (N), oxygen atoms (O), sulfur atoms (S) and phosphorus atoms (P). At least one of the first and second heteroatoms is preferably nitrogen.
In one embodiment, an organic ligand of the invention includes at least one nitrogen heterocycle, for example, a substituted or unsubstituted six- or five-membered heterocycle. Included among the six-member rings are substituted or unsubstituted pyridine, pyridazine, pyrimidine, pyrazine, triazine and tetrazine rings. Among the five-member rings are substituted or unsubstituted pyrazole, benzopyrazole, imidazole, benzimidazole and triazole rings.
In a preferred aspect, a ligand of the invention is neutral in charge and joins two or more heteroatoms separated by at least one intervening atom. At least one of the heteroatoms binds to a transition metal moiety with another heteroatom substantially free to interact with one or more reactant molecules, e.g., water or alkyne. Such ligands are conveniently provided by covalently linking one or more heterocyclic ring(s) to one or more heteroatom(s) outside the ring. The heteroatom(s) outside the first heterocycle can also be present in a ring structure, but need not be. Judicious selection of heteroatoms outside a ring structure can afford an economical and straightforward synthesis of the ligand.
In a particularly preferred aspect of the invention, a ligand covalently links an N heterocyle with a heteroatom different from N, e.g., P or S, outside the heterocyclic ring.
Representative organic ligands in accordance with the present invention are shown by the following structures, wherein xe2x80x9cnxe2x80x9d is an integer independently selected from one or two, and each R is an independently selected monovalent radical, such as discussed hereinbelow: 
Additionally, organic ligands in accordance with the present invention may be selected from: 
Analogous structures wherein the 2-thiopyridyl group(s) are replaced by 2-thioimidazole groups are also included.
Still further, the present organic ligands may be selected from 
wherein L is selected from S, NH, NR, P, N, SR, PR and PR2, xe2x80x9cmxe2x80x9d is an integer selected from 1, 2 or 3, and each R is independently selected from monovalent radicals, preferably monovalent substantially hydrocarbyl radicals.
In another embodiment, the organic ligand contains pyridyl groups conjoined by amido linkages, such as according to the following structure: 
In a preferred aspect of the invention, that is, with respect to hydration of terminal alkynes, a ligand molecule is selected so as to afford a transition metal complex represented by the following formulas: 
In these formulas, M represents a transition metal atom, Ln represents generic solubilizing ligands of the metal, and L and N together represent a chelating ligand. In the Lxe2x80x94N chelating ligand, N is preferably part of a heterocycle and L is a xe2x80x9csoftxe2x80x9d heteroatom, such as P, S, N, As or Se, separated from N (which can be O) by one atom. As demonstrated herein, the chemical cooperativity generated by such a transition metal complex can afford novel catalytically driven reactivities, such as in the anti-Markovnikov hydration of terminal alkynes.
Utilizing the design principle outlined above, a substituted 2-(diphenylphosphino)imidazole ligand 1 is prepared in 51% yield by lithiation of 4-tert-butyl-1-methylimidazole at C-2, followed by quenching with ClPPh2. Two moles of 1 rapidly displace two acetonitrile ligands from CpRu(CH3CN)3 OTf in the presence of 5 equivalents water to give (after crystallization) a 98% yield of catalyst 2, the structure of which has been determined by X-ray crystallography. The molecule has a piano stool structure having stable hydrogen bond network, wherein the two Nxe2x80x94H distances are unequal. However, solution NMR at ambient temperature shows that both phosphines are equivalent, so a rapid conformational change is proposed. This reaction is illustrated in the following scheme: 
A transition metal moiety of the present invention is partially complexed by at least one of the present organic ligands. The transition metal moiety may be a moiety of a metal selected from Group 1B metals, Group IIB metals, Group IIIB metals, Group IVB metals, Group VB metals, Group VIB metals, Group VIIB metals and Group VIIIB metals. Preferably, the transition metal moiety includes a metal selected from chromium, manganese, iron, cobalt, nickel, copper, zinc, zirconium, niobium, molybdenum, ruthenium, rhodium, palladium, silver, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum and gold. For alkyne hydration, the transition metal moiety preferably contains ruthenium.
The present transition metal complexes preferably are soluble in the liquid medium in which such complexes are present or are used. The organic ligands may include one or more substituents, for example, one or more polar substituents and/or non-polar substituents, effective to increase the solubility of the ligand/transition metal complex in a given liquid medium. In addition, the present compositions may include one or more other or additional components, such as silver or thallium salts, acids, bases and the like, in an amount effective to interact with or otherwise affect the complex, for example, to activate the complex and/or to enhance the activity of the complex to facilitate a desired chemical reaction.
The present invention includes within its scope the present ligands and complexes as described herein and any and all substituted counterparts thereof. For example, unless otherwise expressly disclosed to the contrary, one or more of the hydrogen (H) substituents included in the present ligands can be replaced by another monovalent radical, such as a hydrocarbyl radical. Such substituted ligands, as well as the ligands with the hydrogen substituents, are included within the scope of the present invention. In addition, any and all isomers, tautomers, enantiomers, and mixtures thereof of the present ligands are included within the scope of the present invention.
Examples of monovalent radicals that may be included as substituents in the present ligands, for example, as the R groups, include, but not limited to, monovalent hydrocarbon or hydrocarbyl groups, such as alkyl, alkenyl, alkynyl, aryl, alkyl aryl, alkenyl aryl, alkynyl aryl, aryl alkyl, aryl alkenyl, aryl alkynyl and cyclic monovalent hydrocarbon groups; halo such as F, Cl, Br and I; NH2; NO2; alkoxy; alkylthio; aryloxy; arylthio; alkanoyl; alkanoyloxy; aroyl; aroyloxy; acetyl; carbamoyl; alkylamino; dialkylamino; arylamino; alkylarylamino; diarylamino; alkanoylamino; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; alkylsulfonylamido; azido; benzyl; carboxy; cyano; guanyl; guanidino; imino; phosphinyl; silyl; thioxo; uredido or vinylidene or where one or more carbon atoms are replaced by one or more other species including, but not limited to, N, O, P, or S. The term xe2x80x9csubstantially hydrocarbyl radicalxe2x80x9d as used herein refers to a radical in which the number of carbon and hydrogen atoms are at least about 50%, and preferably at least about 70%, or at least about 80%, of the total number of atoms in the radical.
The present invention includes methods for producing a hydrolysis product. Such methods comprise contacting a hydrolysis reactant in the presence of a composition in accordance with the present invention in an amount effective to facilitate the hydrolysis of the hydrolysis reactant to the hydrolysis product. This contacting occurs at effective hydrolysis conditions. Such hydrolysis reaction conditions vary widely depending on many factors, such as the reactants and complex being employed, the concentrations of the reactants and complex, the desired product and other factors. However, such reaction conditions are not of critical importance in the present invention and may be selected from conditions conventionally used in similar reactions. Therefore, a detailed presentation of such conditions is not set forth herein.
The hydrolysis reactant preferably is selected from compounds including amide bonds, nitrites, phosphate esters, and cyanide ions.
Compounds including amide bonds which may be hydrolyzed in accordance with the present invention include, but are not limited to, formamide, acetamide, N-methylacetamide, N,N-dimethylacetamide, N,N-diethylacetamide, propionamide, N-methylpropionamide, N,N-dimeethylpropionamide, N,N-diethylpropionamide, butyramide, N-methylbutyramide, N,N-dimethylbutyramide, acrylamide, N-methylacrylamide, N,N-dimethylacrylamide, benzamide, N-methylbenzamide, N,N-dimethylbenzamide, N,N-diethylbenzamide, o-, m-, and p-toluamides and their N-alkylated derivatives, acetanilide, o-, m-, and p-acetotoluidides, 2-acetamidophenol, 3-acetamidophenol, 4-acetamidophenol, N-acylated amino acids, glycylglycine, alanylalanine, and other polypeptides and proteins.
Nitriles which may be hydrolyzed in accordance with the present invention include, but are not limited to, linear or branched saturated alphatic C2-C18 mono- and C3-C19 dinitriles and phenyl derivatives thereof, C4-C13 saturated alphatic mono- and C5-C14 dinitriles, C3-C18 linear or branched olefinically unsaturated alphatic nitrites, C6-C13 olefinically unsaturated alicyclic nitrites, C7-C14 aromatic mono- and dinitriles C6-C8 heterocyclic nitrogen and oxygen mononitriles, C3-C4 cyanoalkanoic amides, C2-C12 saturated aliphatic cyanohydrins or hydroxynitriles, and mixtures of the above-described nitrites.
Specific examples include, but are not limited to, acetonitrile, propionitrile, buytronitrile, acrylonitrile, benzonitrile, and substituted derivatives.
Phosphate esters which may be hydrolyzed in accordance with the present invention include, but are not limited to, trialkyl phosphates, triaryl phosphates, dialkyl aryl phosphates, alkyl diaryl phosphates, dialkyl phosphates including DNA and RNA derivatives, diaryl phosphates, alkyl aryl phosphates, alkyl phosphates, aryl phosphates, and analogous phosphonic acid derivatives.
Further, the present invention includes methods for converting carbon dioxide. Such methods comprise contacting carbon dioxide in the presence of a composition in accordance with the present invention in an amount effective to facilitate the conversion of the carbon dioxide to a conversion product. The contacting occurs at effective carbon dioxide conversion conditions. Such reaction conditions vary widely depending on many factors, such as the complex being employed, concentrations of the carbon dioxide and complex, the desired product and other factors. However, such conditions are not critical in the present invention and may be selected from conditions conventionally utilized in similar carbon dioxide conversion reactions. Therefore, a detailed presentation of such conditions is not set forth here.
The carbon dioxide conversion product preferably is selected from ureas, carbamates and carbonates.
Another group of chemical reactions facilitated by the present metal complexes is illustrated by the reaction of alkenes with water to produce the corresponding alcohol.
Without wishing to limit the invention to any particular theory of operation, it is believed that the reaction between water and ethylene can be facilitated using the present metal complexes in accordance with the mechanism given below: 
Similar reaction mechanisms can be envisioned for reactions of other alkenes or alkynes with water, alcohols, ammonia and amines. These reactions are conducted by contacting the reactants together with the complex in accordance with the present invention at effective reaction conditions to obtain the desired product or products. Such reaction conditions can vary widely depending on many factors, such as the reactants and complex being employed, the concentrations of the reactants and complex, the desired product or products and other factors. However, such reaction conditions are not of critical importance in the present invention and may be selected from conditions conventionally used in similar reactions. Therefore, a detailed presentation of such conditions is not set forth here.
Nonetheless, a representative reaction and conditions for the hydration of terminal alkynes is set forth below: 
In this reaction, compound 2 is by far the best catalyst to date for the hydration of terminal alkynes to give aldehydes, rather than the isomeric ketones, showing selectivities of up to 1000 to 1.
The following mechanism is proposed to account for the observation of anti-Markovnikov hydration of alkynes: 
It has been proposed that ketone products are the result of attack of water on alkyne xcfx80-complexes such as B. In contrast, for aldehyde formation, likely intermediates include complexes with ligands such as alkyne (B), vinylidene (C), hydroxycarbene (D), or acyl and hydride (E). Reductive elimination from E could lead to aldehyde product. Any of the conversions between A and E could conceivably be aided by the presence of suitably-placed proton or hydrogen-bond donating groups; moreover, aldehyde production could proceed by acyl protonation in an alternative intermediate (F).
The present ligands can be produced from inexpensive and readily available materials, using chemical synthesis techniques well known in the art. To illustrate, many of the present ligands are derived from or based on pyrazole, and can be produced following one of two synthetic routes. In the first route, pyrazole is converted to an electrophilic precursor, whereas in the second route the pyrazole precursor is the nucleophile.
Preparation of Electrophilic Pyrazole Precursor
Pyrazole 1 is converted into chloride 4 in accordance with the following reaction sequences: 
It has been found that an organic solvent is unnecessary in the first step wherein the yield exceeded 95%. The protected pyrazble can then be lithiated with two equivalents of an alkyllithium, such as n-butyllithium, and the pyrazole moiety is than alkylated with formaldehyde. Subsequent deprotection in hydrochloric acid yielded 3. Alcohol 3 is then converted to chloride 4 with thionyl chloride, as noted above.
Use of the Electrophilic Pyrazole Precursor
Pyrazole ligands can be prepared in accordance with the following general reaction: 
The desired ligand 5 can be obtained using three equivalents of lithium diphenylphosphide. Lithium thiomethoxide and sodium disulfide also can be used, giving ligands 6 and 7, respectively. Further, this synthetic route gives access to mono-pyrazole ligands with the general structure of 5 and 6 and (bis-pyrazole)-ligands, such as 7. By changing the R substituent and the tethered ligating atom, a library of ligands with varying steric hindrances and electronic environments can be produced. In addition, solubility properties of the resulting metal complexes can be drastically altered with the use of thiols, such as commercially available 2-mercaptoethane-sulfonic acid sodium salt or 2-mercaptoethanol.
Direct Alkylation of Nucleophilic Pyrazole Precursors
The pyrazole moiety as a carbon nucleophile can be used on electrophiles to obtain pyrazole-based ligands in a one-pot synthesis. Examples of such ligands include compounds 9-11. 
Preparation of Isoelectronic and Isosteric Pyrazole Ligands Incapable of Hydrogen Bonding and Proton Transfer
Isoelectronic and isosteric ligands can be prepared according to a synthetic route illustrated below: 
These ligands provide complexes not capable of hydrogen bonding when chelated to a metal through phosphorus and the unsubstituted nitrogen.
A range of transition metals with varying oxidation states can be complexed with the present ligands, for example, using the following general reaction schemes: 
In one embodiment, the metal has an oxidation state that is unlikely to oxidatively add to the nitrogen-hydrogen bond of a pyrazole moiety. In addition, the formation of stereoisomeric products preferably is reduced. The metals selected preferably are those likely to give four-coordinate complexes, an example of which is Pd(II), as shown by the following complexation reactions: 
In another embodiment, the metal""s oxidation state and structural criteria described above is retained and, in addition, the metals are selected based on a change in the relative pKas of their respective aquo-metal ions. Examples include metals such as platinum(II), zinc(II), and nickel(II), which have aquo-metal ions with pKas of 4, 9 and 10, respectively, whereas the aquo-metal ion of palladium(II) has a pKa of 2.
Metals capable of making hexa- or penta-coordinated complexes may be employed. Examples include chromium, manganese, iron, cobalt, copper, zinc, molybdenum, ruthenium, rhenium, palladium, silver, hafnium, tantalum, tungsten, rhodium, osmium, iridium, platinum and gold. Still more preferably, the transition metal moiety is a moiety of a metal selected from iron, cobalt, copper, zinc, palladium and ruthenium.
The complexes can be substituted with various ligands such as triflate, acetate, water or alcohol. The ligand selections allow adjusting the solubilities of the complexes to enable the hydrolysis of amides, phosphodiesters and nitriles and the addition to carbon dioxide to be conducted in polar or nonpolar solvents.
The present complexes are effective as hydrolysis reagents or reaction facilitators, such as catalysts. For example, it has been found that the complex 19, set forth below, is catalytic toward the hydrolysis of N,N-dimethylacetamide and gives a more than 9% yield of the hydrolysis products: 
However, when complex 17 noted previously is used with dimethylformamide in acetonitrile and water at 75xc2x0 C., amide cleavage products in 4% yield are provided, while complex 19 is found to be inactive. Although these reactions are slow and only two catalytic turnovers were achieved, these results are preliminary in nature. The conditions for the hydrolysis can be adjusted to provide enhanced results.
Hydration of Terminal Alkynes
The hydration of alkynes historically requires catalysis by strong acids and environmentally objectionable Hg(II), or transition metal salts (RuCl3, RhCl3, PtX2, NaAuCl4), and all of is these conditions give Markovnikov addition of water to the terminal alkyne, with formation of the methyl ketone. Anti-Markovnidov hydration can be achieved indirectly by addition of a stoichiometric amount of a borane or silane Bxe2x80x94H or Sixe2x80x94H bond, followed by oxidation. Thus far, the only report of catalytic anti-Markovnikov hydration of terminal alkynes is the work of Tokunaga and Wakatsuki, who reported the combined use of (C6H6)RuCl2(C6F5PPh2) (10 mol %) and C6F5PPh2 (30 mol %) typically gave aldehydes in 50-75% yield, with aldehyde-to-ketone selectivities of about 10 to 1. Hindered alkynes such as phenyl- or tert-butylacetylene gave less than 2% yields of product.
In contrast, we report that (compound 2) works even for tert-butylacetylene at the 2% level, giving yields in excess of 90%. Reactions of 2 with terminal alkynes were examined under the same conditions in order to assess the scope and limitations of the method. Alkyl-substituted alkynes work the best. A tert-butyl group slows hydration but on heating at about 90xc2x0 C., aldehyde is formed in 91% yield. In contrast, the Tokunaga-Wakatsuki system gave 0.9% yield of aldehyde. Phenylacetylene reacts about as sluggishly as tert-butylacetylene, but in this case NMR spectroscopy confirms that 2 mol % 2 disappears after 21 h and hydration stops unless additional catalyst is added. (See Table 1 hereinafter)
Remarkably, alkynes with propargylic oxygen substituents are tolerated. Substrates with acid-sensitive protecting groups such as t-BuMe2Si and tetrahydropyranyl are hydrated to give aldehydes made previously in multistep syntheses.
It is anticipated that, analogously to the addition of water to terminal alkynes, primary alcohols and amines can be catalytically added to the site of unsaturation following the cooperative scheme described hereinabove.
In conclusion, clear evidence is provided that the cooperative effects of a Ru(II) center and two imidazole groups on phosphine ligands create a superior single-component catalyst for the anti-Markovnikov hydration of terminal alkynes under near-neutral reaction conditions. Improvements in catalyst design, the mode of catalyst deactivation, and the extension of this design principle to other structures and reactions are all topics of active investigation in these laboratories.
Preferred ligands for use in the aforementioned addition reactions include those mentioned previously above. Also preferred are ligands containing one or more imidazole groups as the sole heterocycle(s) in the molecule, or in conjunction with one or more pyridyl groups. A partial compilation of these preferred ligands is illustrated hereinbelow: 
The following non-limiting examples illustrate certain aspects of the present invention.